Studies on conformationally restricted, disiloxane bridged analogues of the enkephalins

Abstract

Solution-phase synthesis of protected [Ser², Ser⁵]- and [D-Ser², Ser⁵]-enkephalins, followed by treatment with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane [Prⁱ₂Si(Cl)–O–Si(Cl)Prⁱ₂] in base have yielded cyclic bridged disiloxane analogues showing biological activity in an in vitro assay. Highfield ¹H n.m.r. studies augmented by n.O.e. difference spectroscopy, temperature dependence studies of the amide protons, and the use of computer graphics support the presence of a 2→5 H-bonded β-bend conformation for the most biologically potent of the cyclic analogues.